Five-time champion Serena Williams has reached her first Grand Slam quarter-final of 2014 at the US Open, while Canadian poster girl Eugenie Bouchard, struggling in the heat and humidity, was knocked out.

World number one Williams, the two-time defending champion, eased past world No.50 Kaia Kanepi 6-3 6-3 on Monday for a fourth win over the Estonian.

She goes on to face fellow 32-year-old Flavia Pennetta of Italy in a clash of the two oldest remaining players in the draw.

“It’s my first quarter-final of the year at the majors – at last I did it,” said the American, who had fallen in the fourth round in Australia, the third round at Wimbledon and suffered a second round French Open exit.

“It was a tough match today. Kaia hits the ball very hard and moves the ball around really well. I wanted to stay relaxed and told myself that whatever happens, Serena, you’re still in the doubles.”

Seventh seeded Bouchard was at the centre of a medical drama on Louis Armstrong court when she had to have her blood pressure and temperature taken in her 7-6 (7-2) 6-4 defeat to Russian 17th seed Ekaterina Makarova.

Wimbledon runner-up Bouchard called the medical timeout at 2-3 down in the second set when she was obviously struggling in the 31C heat and humidity running at 60 per cent.

She slipped 4-2 down, broke back for 4-3 but the left-handed Makarova was too strong for the ailing Canadian as she booked a spot in the last-eight for the second successive year.

Bouchard’s defeat ended her run of having reached at least the semi-finals at all the majors this year and also means that for the first time since 1977, the four Grand Slam women’s championship matches will have featured eight different players.

Makarova next faces either former world number one Victoria Azarenka, the runner-up to Williams in 2012 and 2013, or Serbian qualifier Aleksandra Krunic, ranked at 145.

Italian 11th seed Pennetta reached her fifth quarter-final in New York with a 7-5, 6-2 victory over Australian 29th seed Casey Dellacqua.

Pennetta made the semi-finals in 2013, where she was defeated by Azarenka, and despite having a 5-0 losing record against Williams, she refuses to believe that the outcome of the quarter-final is a foregone conclusion.

“Of course she’s better than me, but I still believe I can beat her. If she doesn’t have a good day I can do that,” said Pennetta of an opponent who has dropped just 17 games in four rounds so far.